A common pathway promoting Alzheimer’s and prion disease progression is identified in a paper published online in Nature Medicine. Inhibition of this pathway slows disease progression in mouse models of these diseases, suggesting a single drug targeting this pathway may be beneficial in treating both diseases.
In Alzheimer’s and prion disease, amyloid precursor protein and cellular prion protein are cleaved at the cell surface, respectively. A protective pathway, termed alpha-secretase cleavage, processes these proteins into a form that precludes formation of the toxic proteins that accumulate with disease.
Benoit Schneider, Jean-Marie Launay and colleagues report that alpha-secretase activity is reduced in mice infected with prions or genetically altered to develop Alzheimer’s-like disease. This is associated with increased activity of the kinase PDK1 in the brain of individuals with Alzheimer’s disease and in mice with these diseases. Inhibition of PDK1 in mice, either pharmacologically or genetically, protects neurons from the toxic effects of infectious prions and amyloid-beta and promotes the protective alpha-secretase processing pathway. In mice infected with prions, inhibition of PDK1 delays disease progression, extending survival and reducing motor impairment. The same inhibitor, when given to three different transgenic mouse models of Alzheimer’s disease, attenuates the development of Alzheimer’s disease-like pathology and memory impairment.